Morphine and many of its derivatives are metabolized by the liver with the removal of a methyl group to give the N-demethyl or normorphine product. It is unclear what properties of the drug determine the rate of metabolism. One property which is felt to affect metabolism is the solubility of these agents in organic solvents. During the current year, in order to study the importance of this property on drug metabolism, we have synthesized a series of morphine derivatives in which the phenolic group has been alkylated; that is hydrocarbon chains with two to 10 carbons have been attached to the hydroxyl group. We have then examined how the hepatic endoplasmic reticulum, the organelle of the liver which metabolizes these drugs, is able to remove the N-methyl group. In spite of the fact that the added alkyl groups are distant from the N-methyl group, they still have profound effects on its removal. As the chain length is increased the affinity of the endoplasmic reticulum for the substrate increases so that the 2-carbon derivative binds with one-fifth the affinity of the 8-carbon. Conversely, the rate of metabolism declines with increasing chain length so that the maximal rate for the 8-carbon is about one-fifth of the 2-carbon. Further, the 9- and 10-carbon derivatives showed marked reduced metabolism due to the solubilization of the particles of the endoplasmic reticulum. These data suggest that the metabolism of drugs will be markedly altered by changes in their physicochemical properties. Such changes should be considered in the design of drugs in order to obtain drugs which can be administered at convenient intervals. If the chain is too short, they are very rapidly metabolized and require frequent dosing. On the other hand, if the chain is too long, they will have such a long half life that the drug will build up and cause toxicity.